Sri Ganeshaya namaha ABSTRACT Ziconotide (-conotoxin of size ~3kDa) is a potent drug used for the treatment of chronic pain. It is currently administered only using intrathecal pump owing to the poor bioavailability and profound side effects associated with systemic administration. However, not many people are able to derive its benefit due to complications associated with the intrathecal delivery. Therefore, there is an urgent, unmet need to develop an alternative, noninvasive, patient compliant and effective method of delivering ziconotide to cerebrospinal fluid (CSF). In addition, there is need to develop drug delivery systems which can sustain the retention of drug in CSF to prolong its pharmacological activity. We hypothesize that ziconotide could be delivered to CSF via intranasal administration and the use of appropriate barrier modulating agents would significantly improve its bioavailability to CSF. Further, we also hypothesize that nano co-micellar systems would significantly improve the bioavailability and prolong the retention time of ziconotide in the CSF. We propose four specific aims to assess our hypotheses. In aim 1, we propose to develop novel intranasal drug delivery systems, incorporated with appropriate barrier modulating agents (BMAs) to deliver ziconotide to the cerebrospinal fluid. The permeation of drug and drug-TPGS nano co-micelles across the olfactory mucosa will be investigated in vitro, in presence and absence of BMAs. Three lead (in situ gelling solution) formulations will be developed using suitable polymers to facilitate prolonged retention and drug delivery. In aim 2, we propose to investigate the pharmacokinetics of ziconotide in CSF, following intranasal administration of lead formulations. The lead formulations will be administered intranasally in sprague dawley rats, the drug in the spinal fluid will be sampled at different time points and the drug will be measured by radioimmunoassay. The composition of the formulation will be modified to achieve effective levels of drug in the CSF. In aim 3, we plan to investigate the safety/toxicity of the lead intranasal formulations in rat model. Following frequent and prolonged administration of the formulation, the nasal mucosa, olfactory mucosa, olfactory bulb, brain and spinal cord will be isolated and subjected to histological investigations. In addition, the immunohistochemistry studies would help us understand the pathways of absorption of ziconotide. In aim 4, we propose to investigate the pharmacodynamic efficacy of intranasal formulations in rats. The selected lead formulations will be subjected to hind paw and orofacial formalin tests in rat model. The formalin induced flinch response in the paw will be recorded using automated nociception analyzer and manually in facial formalin test. The group to which ziconotide is administered intrathecally will serve as positive control. The successful completion of the proposed project will result in a novel mode of delivery of ziconotide to CSF for rapid and prolonged effect in the treatment of chronic pain. We strongly believe that development of an intranasal formulation of ziconotide would significantly improve the quality of life of patients suffering from chronic pain and increase the size of the patient population that would benefit from this drug.